DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims Status
Claims 8-9, 11-13, 16 is/are cancelled. Claims 1-7, 10, 14-15 is/are currently pending. Claims 1-6, 10, 14-15 is/are under examination.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
The information disclosure statement filed 05/14/2025 fails to comply with 37 CFR 1.98(a)(3)(i) because it does not include a concise explanation of the relevance, as it is presently understood by the individual designated in 37 CFR 1.56(c) most knowledgeable about the content of the information, of each reference listed that is not in the English language. It has been placed in the application file, but the information referred to therein has not been considered. NPL#2 appears to be written in Russian, with no explanation of relevance in the English language.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
“Table 2” on page 46 recites sequences for “has-miR-34a-5p”, “has-miR-125b-5p”, “has-miR-146a-5p”, and “has-miR-1307-3p” with no corresponding SEQ ID NO present in the specification. The miRNA sequences recited in “Table 1” on page 46 and “Table 3” on pages 46-47 are recited with corresponding SEQ ID NOs in “Table 1” on pages 18-20.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. Hyperlinks were found on page 13 line 9 and page 30 line 2. Applicant is advised to review the specification in order to ensure that all hyperlinks are identified and appropriately removed.
The disclosure is objected to because of the following informalities: two tables are labeled as “Table 1”: one spanning pages 18-20, the other on page 46.
Appropriate correction is required.
Claim Objections
Claim 15 is objected to because of the following informalities: “gene” in line 2 should be the plural “genes”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
112(b):
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 4 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 4 recites the broad recitation “0.1-10000 pmol/L”, and the claim also recites “o.1-1000 pmol/L”, “1-1000 pmol/L”, “10-1000 pmol/L”, and “1000-1000 pmol/L”, which are the narrower statements of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
112(a):
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description:
Claims 1-2, 4-7, 10, 14 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V, v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Eiees., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641,1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F. 2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it”).
Claims 1 and 10 recite a “nutritional composition” and claim 2 encompasses “fortifiers” comprising miR-3126. The breadth of these terms creates a massive genus of compositions.
A “nutritional composition” is defined in the specification (page 4) as “a composition which nourishes a subject” and which “does not include natural milk of human or animal origin, i.e. the nutritional composition is not natural human or animal milk.” Page 5 of the specification broadly describes “suitable nutritional compositions” as “foodstuffs, drinks, supplements, drug bases and animal feeds…infant formula, a baby food, an infant cereal composition, a fortifier such as a human milk fortifier, or a supplement…may be an enteral nutritional composition…may be a hypoallergenic nutritional composition”. The disclosure provides descriptions of infant formula, supplements, and milk and infant formula fortifiers, and the applicants provided evidence that miRNAs in breast milk are absorbed by the infant gastrointestinal system. However, the applicants have not provided evidence in the disclosure that all types of nutritional compositions can or have been modified to comprise a human microRNA such as miR-3126-3p or miR-3126-5p. A search of the art does not provide evidence that any type of nutritional compositions can be modified to comprise human microRNAs. Zhang (2019), as an example, teaches that some nutritional compositions derived from living organisms comprise endogenously-expressed microRNAs (for example, plant products comprise microRNAs expressed by the plants the products are derived from, and human and animal milks comprise microRNAs produced by the animal which produced the milk). Zhang further teaches that different nutritional compositions comprise distinct forms of stabilizing microRNAs, and that synthetic microRNAs are unstable during food processing, cooking, and digestion (page 713). Based on the teachings of Zhang, a search of the field, and the contents of the present disclosure, an artisan would not be able to determine that the applicants were in possession of nutritional compositions of all possible forms or types wherein the nutritional compositions further comprise a human microRNA, including miR-3126-3p or miR-3126-5p, wherein the human microRNA is present in any form, including unpackaged (see Zhang; a “large fraction” of microRNAs found in animal and human milks are packaged in exosomes, conferring stability, page 713), and wherein the nutritional composition is not human or animal milk. Such an artisan would recognize that, in order to stabilize a microRNA such that the microRNA is not degraded within a nutritional composition and within a human gastrointestinal system, the microRNA would need to be modified or packaged, with consideration to the characteristics of and environment within the nutritional composition and the human gastrointestinal system. As such, a description of one type of nutritional composition formulated to comprise a specific microRNA cannot describe all other types of nutritional compositions.
A “fortifier” is described in the specification (pages 6-7) as a term that “may refer to liquid or solid nutritional compositions suitable for mixing with breast milk or infant formula”. As a “fortifier” may be described as such, this is not a limiting definition of the term “fortifier”. The art defines “fortifier” broadly as any nutritional composition which can be added to food (not limited to breast milk or infant formula) in order to add nutritional benefits (see Purefood, 2017). The specification does not describe embodiments of “fortifiers” which are not breast milk or infant formula fortifiers, through descriptions of structure or functional characteristics. The specification only describes embodiments of nutritional fortifiers that are breast milk or infant formula fortifiers, and as such, the full breadth of the genus of nutritional “fortifiers” is not described.
The working examples described in the disclosure do not describe compositions comprising miR-3126-3p or miR-3126. “Example 1”, pages 44-47, describes the identification of microRNAs present in unaltered human breast milk, including miR-3126-5p but not miR-3126-3p or the precursor microRNA miR-3126. “Example 2”, pages 47-51, describes in vitro cell culture medium compositions comprising miR-3126-5p “mimic” (see page 48, lines 12-13). While the specification discloses that naturally-occurring human breast milk comprises the mature microRNA miR-3126-5p, the specification does not disclose that naturally-occurring human breast milk comprises the mature microRNA miR-3126-3p or the unprocessed microRNA miR-3126 (Table 1). The in vitro compositions described on page 48 of the specification only comprise miR-3126-5p, not miR-3126 or miR-3126-3p. As such, the specification only describes compositions comprising miR-3126-5p.
The specification only provides a method for producing a claimed nutritional composition by “blending together a protein source, a carbohydrate source and a fat source in appropriate proportions” to produce a liquid, then adding the microRNA, then optionally dehydrating to produce a powder (page 43). While “nutritional composition” as defined in the specification encompasses any nutritional composition—including, for example, vegetables, fruits, and milk products like butter and cheese, so long as the composition is not human or animal milk—the sole description of a method of producing the claimed nutritional composition only describes a limited number of species of nutritional compositions, including infant formula. An artisan would not be able to determine, based on the descriptions provided in the disclosure regarding formulation and production of nutritional compositions, the breadth of the term “nutritional composition”, the evidence provided by the applicant and taught by the art regarding miRNA in human and animal milk and milk products, and the evidence provided in the working examples, that the applicants were in possession of nutritional compositions comprising miR-3126-5p which cannot be produced by the method described on page 43 of the specification or by processing human or animal milks (e.g., cheese or butter produced from human or animal milk).
According to the MPEP § 2163, "The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus (see i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutsch land GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.")."
The disclosure, in the context of what was known in the art and how terms in the claim limitations are defined in the art and in the specification, only sufficiently describes nutritional compositions produced by blending a protein source, a carbohydrate source, and a fat source and adding miR-3126-5p or produced by the processing of human or animal milk comprising miR-3126-5p, which encompasses infant formulas and a narrow scope of nutritional “fortifiers” and “supplements”; as described above, no other embodiments of nutritional compositions are sufficiently described such that an artisan would be able to determine that the applicants were in possession of the full scope of the claimed invention of claims 1-2 and 10, and of claims 4-7 and 14, which depend on claims 1 and 10 and do not sufficiently narrow the breadth of the claimed nutritional compositions such that the claims only recite sufficiently-described nutritional compositions.
Enablement:
Claims 10 and 14 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The factors to be considered in determining whether a disclosure would require undue experimentation include:
A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims:
With respect to claim breadth, the standard under 35 U.S.C. §112, first paragraph, entails the determination of what the claims recite and what the claims mean as a whole. As such, the broadest reasonable interpretation of the claimed method is that administration of a nutritional composition comprising miR-3126 to a subject, including an infant, results in protection of gastrointestinal health, promotion of gut barrier development and function, promotion of growth and development, reduction of risk of development of infections, lymphoproliferative disorders, allergic diseases, or inflammatory diseases. A skilled artisan would not know how to use the method with a reasonable expectation of success based solely on what is disclosed in the specification.
The amount of direction provided by the inventor and the level of predictability in the art:
The specification teaches miRNA in human breast milk “may promote healthy growth and development of [an] infant” (page 1); that genes whose expression is shown in vitro to be modulated by miR-3126-5p may promote gastrointestinal health, growth and development, the development of the immune system in infants (pages 25-32; in vitro results shown in Table 4, page 50). The language used in the specification to describe health or developmental benefits of administering nutritional compositions comprising miR-3126-5p is merely prophetic, with no direct evidence that administration of nutritional compositions comprising miR-3126-5p affects gene expression in a subject the same as administration of miR-3126-5p in vitro, and with no evidence that the degree of gene expression modulation that miR-3126-5p may produce in vivo would be sufficient to produce the claimed health and developmental effects. The specification furthermore does not provide evidence of gene expression modulation by, or health or developmental benefits of, miR-3126-3p or precursor miR-3126. The art at the time of filing does not provide evidence that nutritional compositions comprising miR-3126-5p, miR-3126-3p, or precursor miR-3126 provide specific health or developmental benefits to subjects who consume the compositions. Ahern (2019) teaches that it was yet unclear, at the time of filing, whether all miRNAs present in milk were stable in the milk or in the gastrointestinal tract or during pasteurization and homogenization, whether all miRNAs present in milk were absorbed during digestion and produced health or developmental effects, and whether infant formula should be modified to comprise miRNAs (page 89). The present disclosure does not provide evidence that miR-3126-5p, miR-3126, or miR-3126-3p are stable through pasteurization and homogenization, are stable in milk and in the gastrointestinal tract, are absorbed during digestion, or modulate gene expression, health, or development in vivo. The specification as filed thus does not provide guidance that overcomes this unpredictability within the art.
The existence of working examples:
What is enabled by the working examples is narrow in comparison to the breadth of the claims: The specification discloses in vitro administration of miR-3126-5p “mimic” to Caco2 cells, wherein miR-3126-5p “mimic” is present in an in vitro cell culture growth medium composition (page 48). As claim 10 only reads on methods of modulating gastrointestinal health, development and function, development, function, or health of the immune system, or general growth and development of “a subject”, claim 10 requires in vivo administration. Claim 14 specifically requires that the subject is “an infant”. The specification does not disclose in vivo methods of administering miR-3126-5p.
The quantity of experimentation needed to make or use the invention:
The standard of an enabling disclosure is not the ability to make and test if the invention works but one of the ability to make and use with a reasonable expectation of success. A patent is granted for a completed invention, not the general suggestion of an idea (MPEP 2164.03 and Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1325-26 (Fed. Cir. 2004). The instant specification is not enabling because one cannot follow the guidance presented therein, or within the art at the time of filing, and practice the claimed method without first making a substantial inventive contribution. Given that the nature of the invention is modulating gastrointestinal, immune, or general health, development, or function of a subject in vivo by administering a nutritional composition comprising miR-3126, a person having ordinary skill in the art would have to perform multiple further experiments, in human trials or in animal models predictive of human digestion and absorption of miR-3126, miR-3126-5p, and miR-3126-3p and of in vivo modulation of gene expression in response to microRNA digestion and absorption, in order to demonstrate the invention could be used with a reasonable expectation of success. The amount of experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine' within the art, and constitutes undue further experimentation in order to use the method with a reasonable expectation of successfully treating any CNS disorder or neurodegenerative disease. Therefore, claims 10 and 14 are rejected under 35 U.S.C. 112, first paragraph, for failing to meet the enablement requirement.
Scope of Enablement:
Claim 15 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for in vitro methods of modulating expression of one or more of ninein, Unc-13 homolog D, Sulfatase 2, IL-32, OXER1, TMEM127, Butyrophilin, Integrin subunit alpha 2, Integrin beta 1, tubulin alpha 4A, tubulin beta 6, tubulin beta 2A, and tubulin beta 2B comprising administering miR-3126-5p to cells cultured in vitro, does not reasonably provide enablement for in vivo methods of modulating expression of one or more of ninein, Unc-13 homolog D, Sulfatase 2, IL-32, OXER1, TMEM127, Butyrophilin, Integrin subunit alpha 2, Integrin beta 1, tubulin alpha 4A, tubulin beta 6, tubulin beta 2A, and tubulin beta 2B comprising administering miR-3126-5p, miR-3126-3p, or precursor miR-3126 to an in vivo subject. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure would require undue experimentation include:
A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims:
With respect to claim breadth, the standard under 35 U.S.C. §112, first paragraph, entails the determination of what the claims recite and what the claims mean as a whole. As such, the broadest reasonable interpretation of the claimed method is that it encompasses modulation of the recited genes’ expression in vitro and in vivo by administration of miR-3126, miR-3126-5p, or miR-3126-3p by any means. A skilled artisan would not know how to use the method with a reasonable expectation of success based solely on what is disclosed in the specification.
The amount of direction provided by the inventor and the level of predictability in the art:
The specification teaches prophetic discussion of miR-3126-5p modulating gene expression in vivo, but does not provide evidence that miR-3126, miR-3126-5p, or miR-3126-3p, administered in vivo, is capable of modulating expression of any of the genes recited in claim 15. The art at the time of filing teaches that it was yet unclear whether microRNAs in milk or formula were stable through processing and digestion of the milk or formula, absorbed by the digestive system of an infant, and produced impacts on health or development of an infant (see Ahern, 2019, page 89). The specification as filed does not provide guidance that overcomes this unpredictability within the art. The specification also only teaches nutritional compositions comprising miR-3126-5p; the specification does not teach other means of administering miR-3126, miR-3126-5p, or miR-3126-3p.
The existence of working examples:
What is enabled by the working examples is narrow in comparison to the breadth of the claims: The specification discloses a method of modulating expression of one or more of ninein, Unc-13 homolog D, Sulfatase 2, IL-32, OXER1, TMEM127, Butyrophilin, Integrin subunit alpha 2, Integrin beta 1, tubulin alpha 4A, tubulin beta 6, tubulin beta 2A, and tubulin beta 2B comprising administering miR-3126 in vitro to Caco2 cells (page 48). The specification does not provide working examples which teach in vivo administration of miR-3126 or miR-3126-3p; the specification also does not provide working examples or evidence which teach that in vivo administration of miR-3126-5p results in the modulation of one or more of ninein, Unc-13 homolog D, Sulfatase 2, IL-32, OXER1, TMEM127, Butyrophilin, Integrin subunit alpha 2, Integrin beta 1, tubulin alpha 4A, tubulin beta 6, tubulin beta 2A, and tubulin beta 2B.
The quantity of experimentation needed to make or use the invention:
The standard of an enabling disclosure is not the ability to make and test if the invention works but one of the ability to make and use with a reasonable expectation of success. A patent is granted for a completed invention, not the general suggestion of an idea (MPEP 2164.03 and Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1325-26 (Fed. Cir. 2004). The instant specification is not enabling because one cannot follow the guidance presented therein, or within the art at the time of filing, and practice the claimed method without first making a substantial inventive contribution. Given that the nature of the invention encompasses in vivo modulation of gene expression by administering miR-3126 by any means, a person having ordinary skill in the art would have to perform multiple further experiments, in human clinical trials or in animal models, in order to demonstrate the invention could be used with a reasonable expectation of success. The amount of experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine' within the art, and constitutes undue further experimentation in order to use the method with a reasonable expectation of successfully treating any CNS disorder or neurodegenerative disease. Therefore, claim 15 is rejected under 35 U.S.C. 112, first paragraph, for failing to meet the enablement requirement.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 4-7, and 15 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more. The claim(s) recite(s) a natural process—the modulation of gene expression by the natural activity of an endogenously-expressed human pre-microRNA (miR-3126) or human miR-3126-5p or miR-3126-3p. This judicial exception is not integrated into a practical application because the claimed judicial exception is not implemented with a particular additional element or step, nor is it transformed or reduced to a different state or thing, nor does it meet any other considerations under MPEP 2106.05(a-h). The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception. The only elements recited in claim 15 are the modulation of gene expression and the use of miR-3126; as a cell is able to use endogenously-expressed pre-miR-3126, miR-3126-5p, or miR-3126-3p to modulate gene expression (see, for example, Li, 2018, and Kim, 2023, provided by the applicant with IDSes filed 01/09/2023 and 05/14/2025, respectively). The only elements recited in claims 1 and 4-7 are a “nutritional composition comprising miR-3126”, wherein a “nutritional composition” excludes human or animal milk and “nourishes a subject” (page 4 lines 25-30), and wherein the nutritional composition comprises miR-3126 at a concentration of 0.1-10,000pmol/L (claim 4) and further comprises one or more miRNAs endogenously expressed in human tissues (claims 5-7).
Claim 15 recites a method of modulating gene expression, which constitutes a process—one of the statutory categories of invention. Claims 1 and 4-7 recite a nutritional composition, which constitutes a product—one of the statutory categories of invention.
Claim 15 recites processes which encompass natural phenomena with no additional steps, as described in MPEP § 2106.04(b)(I). The natural phenomenon is the ability of an endogenously-expressed human pre-miRNA or miRNA (pre-miR-3126, miR-3126-5p, miR-3126-3p) to modulate expression of endogenously-expressed human gene(s) (ninein, Unc-13 homolog D, Sulfatase 2, IL-32, OXER1, TMEM127, Butyrophilin, Integrin subunit alpha 2, Integrin beta 1, tubulin alpha 4A, tubulin beta 6, tubulin beta 2A, and tubulin beta 2). The specification teaches that miR-3126-5p is capable of modulating expression of these genes in human cells (Caco2 cells) (page 48). The art teaches that pre-miR-3126, miR-3126-5p, and miR-3126-3p were known to be endogenously expressed by human cells and to be capable of modulating gene expression in human cells (see Li, 2018, and Kim, 2023). While modulation of one or more of ninein, Unc-13 homolog D, Sulfatase 2, IL-32, OXER1, TMEM127, Butyrophilin, Integrin subunit alpha 2, Integrin beta 1, tubulin alpha 4A, tubulin beta 6, tubulin beta 2A, and tubulin beta 2B by miR-3126, miR-3126-5p, or miR-3126-3p was not described in the prior art, an artisan would recognize that a human cell which endogenously expresses miR-3126, miR-3126-5p, or miR-3126-3p would naturally perform the claimed method of modulation of the expression of one or more of ninein, Unc-13 homolog D, Sulfatase 2, IL-32, OXER1, TMEM127, Butyrophilin, Integrin subunit alpha 2, Integrin beta 1, tubulin alpha 4A, tubulin beta 6, tubulin beta 2A, and tubulin beta 2B by using miR-3126, miR-3126-5p, or miR-3126-3p.
Claims 1 and 4-7 recite products which encompass products of nature as described in MPEP § 2106.04(b)(II). These compositions are tissues, bodily fluids, and cells which endogenously express miR-3126 (claims 1, 4) and one or more of the miRNAs recited in claims 5-7. The specification does not limit the meaning of “nourishment”, and as such, any tissue, cell, or bodily fluid ingested by a subject can be considered to “nourish” the subject. As such, any tissue, cell, or bodily fluid that is not human or animal breast milk is a “nutritional composition”. As miR-3126 is expressed in humans, the claims encompass any human tissue, cell, or bodily fluid that is not human breast milk.
According to Step 2A, Prong Two, set forth in MPEP § 2106.04(II)(A)(2), the claims are next evaluated with respect to whether the judicial exception is integrated into a practical application. These considerations are set forth in MPEP § 2106.05(a)-(h). This analysis turns to the additional steps or elements recited within the claims. Claim 15 does not recite any additional steps or elements beyond what has been determined to be a judicial exception.
There are no additional elements that reflect an implementation with a particular additional element nor is it transformed or reduced to a different state, nor which meets any other considerations under MPEP § 2106.05(a)-(h), such that the claimed method and product amount to significantly more than the judicial exceptions.
For all these reasons, claims 1, 4-7, and 15 are directed to judicial exceptions without significantly more and are rejected.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2, 5-7 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Allen (2011), as evidenced by Raymond (2021) and Purefood (2017).
MPEP §2131.01 provides guidance as to 35 U.S.C. 102 rejections over multiple references. Such rejection has been held to be proper when the extra references are cited to: (C) Show that a characteristic not disclosed in the reference is inherent.
The MPEP states: “To serve as an anticipation when the reference is silent about the asserted inherent characteristic, such gap in the reference may be filled with recourse to extrinsic evidence. Such evidence must make clear that the missing descriptive matter is necessarily present in the thing described in the reference, and that it would be so recognized by persons of ordinary skill.” Continental Can Co. USA v. Monsanto Co., 948 F.2d 1264, 1268, 20 USPQ2d 1746, 1749 (Fed. Cir. 1991) (The court went on to explain that “this modest flexibility in the rule that 'anticipation' requires that every element of the claims appear in a single reference accommodates situations in which the common knowledge of technologists is not recorded in the reference; that is, where technological facts are known to those in the field of the invention, albeit not known to judges.” 948 F.2d at 1268, 20 USPQ at 1749-50.). Note that the critical date of extrinsic evidence showing a universal fact need not antedate the filing date. See MPEP §2124.
Regarding claims 1-2, Allen teaches a nutritional composition, encompassed by the commonly-used definition of “fortifier” (see Purefood, page 2: cheese is a nutritional fortifier), wherein the nutritional composition is cheese made from human breast milk (pages 1-2). Raymond teaches that human breast milk naturally comprises miR-3126-5p (Fig. 2). Thus, the human breast milk used to make the cheese taught by Allen would have naturally comprised miR-3126-5p.
Regarding claims 5-6, Raymond teaches that human breast milk naturally comprises let-7d-3p, miR-196a-5p, miR-187-5p, miR-516a-5p, miR-92b-5p, miR-3184-3p (required by claim 6), miR-22-3p, miR-99a-5p, miR-92a-3p, miR-149-3p, miR-125a-5p, miR-149-3p, miR-193a-5p, miR-320a, miR-320c, miR-151a-3p, miR-375, miR-378a-3p (Figs. 1-2). Cheese made from human breast milk, as taught by Allen, would naturally comprise these miRNA.
Regarding claim 7, Raymond teaches that human breast milk naturally comprises miR-3184-3p (Fig. 2). Cheese made from human breast milk, as taught by Allen, would naturally comprise this miRNA.
Claim(s) 1-2, 5-7 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhang (US20160017321A1).
Regarding claims 1-2, Zhang teaches an oral supplement composition comprising miR-3126 (claims 1-3, 7-9, 15; paragraphs [0037], [0040], [0065]-[0067], [0073]-[0074]).
Regarding claim 5, Zhang teaches that the composition further comprises one or more of miR-let-7c, miR-22, miR-24, miR-25, miR-29a, miR-30a, miR-92a, miR-100, miR-197, miR-30d, miR-181a, miR-181b, miR-205, miR-210, miR-221, miR-125b, miR-125a, miR-149, miR-193a, miR-200a, miR-99b, miR-130b, miR-30e, miR-375, miR-151a, miR-484, miR-146b, miR-652, let-7d, miR-196a, miR-187, miR-516a, miR-92b, miR-3184 (paragraph [0067]).
Regarding claim 6, Zhang teaches that the composition further comprises one or more of let-7d, miR-196a, miR-187, miR-516a, miR-92b, and miR-3184 (paragraph [0067]).
Regarding claim 7, Zhang teaches that the composition further comprises miR-3184 (paragraph [0067]).
Claim 15 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Li (2018; provided by Applicant with IDS filed 01/09/2023), as evidenced by Raymond (2021).
MPEP §2131.01 provides guidance as to 35 U.S.C. 102 rejections over multiple references. Such rejection has been held to be proper when the extra references are cited to: (C) Show that a characteristic not disclosed in the reference is inherent.
The MPEP states: “To serve as an anticipation when the reference is silent about the asserted inherent characteristic, such gap in the reference may be filled with recourse to extrinsic evidence. Such evidence must make clear that the missing descriptive matter is necessarily present in the thing described in the reference, and that it would be so recognized by persons of ordinary skill.” Continental Can Co. USA v. Monsanto Co., 948 F.2d 1264, 1268, 20 USPQ2d 1746, 1749 (Fed. Cir. 1991) (The court went on to explain that “this modest flexibility in the rule that 'anticipation' requires that every element of the claims appear in a single reference accommodates situations in which the common knowledge of technologists is not recorded in the reference; that is, where technological facts are known to those in the field of the invention, albeit not known to judges.” 948 F.2d at 1268, 20 USPQ at 1749-50.). Note that the critical date of extrinsic evidence showing a universal fact need not antedate the filing date. See MPEP §2124.
Regarding claim 15, Li teaches a method of modulation gene expression by administering to a cell in vitro a composition comprising miR-3126 (page 7). Such a method would inherently modulate the expression of one or more of ninein (NIN), Unc-13 homolog D (UNC13D), Sulfatase 2 (IDS), IL-32, OXER1, TMEM127, Butyrophilin (BTN1A1), Integrin subunit alpha 2 (ITGA2), Integrin beta 1 (ITGB1), tubulin alpha 4A (TUBA4A), tubulin beta 6 (TUBB6), tubulin beta 2A (TUBB2A), and tubulin beta 2B (TUBB2B), as Raymond teaches this as an inherent function of miR-3126 (Supplemental Table 3).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-2 and 4 rejected under 35 U.S.C. 103 as being unpatentable over Allen (2011), as evidenced by Raymond (2021) and Purefood (2017).
Regarding claims 1-2, Allen teaches a nutritional composition, encompassed by the commonly-used definition of “fortifier” (see Purefood, page 2: cheese is a nutritional fortifier), wherein the nutritional composition is cheese made from human breast milk (pages 1-2). Raymond teaches that human breast milk naturally comprises miR-3126-5p (Fig. 2). Thus, the human breast milk used to make the cheese taught by Allen would have naturally comprised miR-3126-5p.
Regarding, Raymond does not teach the concentration of miR-3126-5p in human breast milk, required by claim 4. Raymond does teach that macronutrient composition in breast milk varies day-to-day and over the course of lactation (page 95). It would have been obvious to an artisan at the time of filing that the concentration of miR-3126-5p naturally occurring in human breast milk could fall within the range of 0.1-10,000 pmol/L, as a natural variant in macronutrient concentration. As a result, human breast milk cheese as taught by Allen would naturally comprise miR-3126-5p in a variety of concentrations, dependent on individual, daily, and long-term variation in miRNA secretion during lactation, these concentrations including a range of 0.1-10,000 pmol/L.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the appl